The aim of this proposal is to study mechanism-based strategies for enhancing the efficacy of vaccination for the treatment of nicotine dependence in rats. Vaccination of rats against nicotine binds and sequesters nicotine in serum, reduces nicotine distribution to brain, and blocks or attenuates a variety of nicotine-induced behaviors that are relevant to nicotine dependence. These results suggest that vaccination may be useful in the treatment or prevention of nicotine dependence, and a phase I clinical trial has been initiated. However, there are potential limitations to vaccine efficacy, and some effects of vaccination are incomplete. This may be due to the finite amount of antibody that can be elicited by vaccination (and the variability in response among subjects), inability to control the affinity of antibodies elicited by vaccination, or the spectrum of action of vaccination which may target some aspects of nicotine dependence (e.g. reinforcement) better than others (e.g. ongoing withdrawal). This study will examine two general approaches to enhancing the efficacy of immunization; (a) the use of passive immunization with monoclonal nicotine-specific antibodies to investigate the relationship of affinity and dose to efficacy, and to determine whether passive immunization (administration of exogenous antibody) may have therapeutic application of its own as an alternative or supplement to vaccination, and (b) combining vaccination with other interventions that act via complementary mechanisms. Specific hypotheses to be tested are that 1) The efficacy of immunization can be enhanced by optimizing antibody affinity for nicotine, 2) Efficacy can be enhanced by using passive immunization to provide higher doses of antibody than can be achieved with vaccination, 3) Passive immunization with therapeutically effective antibody doses is well tolerated, 4) Vaccine efficacy can be enhanced by combining it with the nicotinic receptor antagonist mecamylamine, or nicotine infusion (simulating nicotine replacement therapy), and 5) Efficacy can be enhanced by combining vaccination with passive immunization, a strategy that could exploit the potential clinical advantages of each. These questions will be studied using a variety of pharmacokinetic and behavioral models including nicotine distribution to brain after acute and chronic nicotine dosing, nicotine self-administration, reinstatement of nicotine responding, nicotine abstinence, and relief of nicotine abstinence by nicotine. These data will expand our understanding of the mechanisms, limitations and clinical potential of both vaccination and passive immunization for the treatment or prevention of nicotine dependence.